更新于：2024-09-19

GABRA2

更新于：2024-09-19

基本信息

别名

GABA(A) receptor subunit alpha-2、GABA(A) receptor, alpha 2、GABRA2

+ [3]

简介

Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:29961870, PubMed:31032849). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:29961870, PubMed:31032849). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (By similarity). The alpha2/beta2/gamma2 receptor exhibits synaptogenic activity whereas the alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity (By similarity).

关联

项与 GABRA2 相关的药物

AN-721

靶点

GABRA2 x GABRA3

作用机制

GABRA2调节剂 [+1]

在研机构

GSK Plc [+1]

原研机构

NTG Nordic Transport Group A/S

在研适应症

疼痛

非在研适应症

焦虑症 [+2]

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

DPX-102

靶点

GABRA2 x GABRA3 x GABRA5

作用机制

GABRA2调节剂 [+2]

在研机构

Damona Pharmaceuticals, Inc.初创企业

原研机构

Damona Pharmaceuticals, Inc.初创企业

在研适应症

癫痫 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

AZD-7325

靶点

GABRA2 x GABRA3

作用机制

GABRA2调节剂 [+1]

在研机构

Avenue Therapeutics, Inc.

原研机构

阿斯利康制药有限公司

在研适应症

失神发作 [+1]

非在研适应症

焦虑 [+2]

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 GABRA2 相关的临床试验

NCT03678129 / RecruitingN/AIIT

Modulation of the Brain Excitatory/Inhibitory (E/I) Balance Through Neuronal Systems in Autism Spectrum Disorder (ASD)

This study investigates the brain response to a single acute dose of a GABAa receptor acting drug (Benzodiazepine or positive allosteric modulator) compared to a single dose of placebo in adults with and without autism spectrum disorder.

开始日期2018-12-07

申办/合作机构

King's College London

NCT03140813 / Completed临床1期IIT

An Initial Double-Blind, Placebo-Controlled Two-Dose Crossover Study of AZD7325 in Adults With Fragile X Syndrome

This study will investigate the safety, tolerability and blood pharmacodynamics of treatment with oral administration of AZD7325 at 5 mg BID, 15 mg BID, and placebo BID, in adults with Fragile X Syndrome. The study also will also investigate measures of efficacy and biomarkers during treatment.

开始日期2018-01-16

申办/合作机构

Children's Hospital & Medical Center

NCT02530580 / Completed临床1期IIT

A Phase I Single Site, Single Dose, Randomized, Double-blind, Placebo Controlled, 2-way Cross-over Biomarker Study Investigating the Effect of the GABA Modulator AZD7325 on Cutaneous Sensation in Healthy Volunteers

GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the human brain. For years, drugs that enhance its effects (e.g., benzodiazepines such as diazepam/Valium) have been used to treat various diseases such as epilepsy, insomnia, anxiety or movement disorders. However, the use of these medications is often compromised because of their side effects, such as sleepiness, memory problems, and addiction.
Therefore, effort has been made to develop drugs that act more selectively in the brain to exert the positive therapeutic effects and are devoid of the unwanted side effects. AZD7325 is one of these drugs. It has been tested in more than 700 people and so far proved to be generally well tolerated. Positron emission tomography (PET) study in humans demonstrated that AZD7325 binds to GABA A receptors in the brain after a single dose. Early clinical studies have shown that it has less sedative and cognitive adverse events as compared with a benzodiazepine lorazepam.
The investigators now wish to evaluate if effects of AZD7325 can be objectively measured in healthy volunteers and to establish which of the drug's outcomes could be utilised for further studies in patients with neurological diseases.
The investigators are especially interested in the effects of AZD7325 on manual dexterity and skin sensation of the hand. This can be assessed by a number of simple non-invasive tests of object manipulation and detection of different sensory stimuli such as touch, vibration, or temperature. Recent studies show that healthy individuals who performed better in similar tasks had more GABA in relevant areas of their brain. If performance in these tasks in healthy volunteers can be improved by enhancing GABA effects in the brain with AZD7325, this would create the grounds for the use of this medication to treat symptoms of certain neurological disorders in which motor control and sensation of the hand is impaired (e.g., polyneuropathy).

开始日期2016-02-01

申办/合作机构

University College London

100 项与 GABRA2 相关的临床结果

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100 项与 GABRA2 相关的转化医学

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0 项与 GABRA2 相关的专利（医药）

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354

项与 GABRA2 相关的文献（医药）

2024-08-01·Neuroscience

Hypothalamic and hippocampal transcriptome changes in AppNL-G-F mice as a function of metabolic and inflammatory dysfunction

Article

作者: Noutsos, Christos ; Gutiérrez Rico, Evelyn ; Poon, Kinning ; Joseph, Patricia

The progression of Alzheimer's disease (AD) has a silent phase that predates characteristic cognitive decline and eventually leads to active cognitive deficits. Metabolism, diet, and obesity have been correlated to the development of AD but is poorly understood. The hypothalamus is a brain region that exerts homeostatic control on food intake and metabolism and has been noted to be impacted during the active phase of Alzheimer's disease. This study, in using an amyloid overexpression App^NL-G-F mouse model under normal metabolic conditions, examines blood markers in young and old male App^NL-G-F mice (n = 5) that corresponds to the silent and active phases of AD, and bulk gene expression changes in the hypothalamus and the hippocampus. The results show a large panel of inflammatory mediators, leptin, and other proteins that may be involved in weakening the blood brain barrier, to be increased in the young App^NL-G-F mice but not in the old App^NL-G-F mice. There were also several differentially expressed genes in both the hypothalamus and the hippocampus in the young App^NL-G-F mice prior to amyloid plaque formation and cognitive decline that persisted in the old App^NL-G-F mice, including GABRa2 receptor, Wdfy1, and several pseudogenes with unknown function. These results suggests that a larger panel of inflammatory mediators may be used as blood markers to detect silent AD, and that a change in leptin and gene expression in the hypothalamus exist prior to cognitive effects, suggesting a coupling of metabolism with amyloid plaque induced cognitive decline.

2024-07-01·Differentiation

Characterization of the zebrafish gabra1 germline loss of function allele confirms a function for Gabra1 in motility and nervous system development

Article

作者: Paz, David ; Estevao, Igor L ; Gil, Claudia B ; Gonzales, Annalise V ; Quintana, Anita M ; Castro, Victoria L ; Grajeda, Brian I ; Reyes-Nava, Nayeli G ; Pinales, Briana E ; Ellis, Cameron C ; Perez, Isaiah

Mutation of the GABRA1 gene is associated with neurodevelopmental defects and epilepsy. GABRA1 encodes for the α1 subunit of the γ-aminobutyric acid type A receptor (GABA_AR), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have been developed to understand the function of GABRA1, but these models have produced complex and, at times, incongruent data. Thus, additional model systems are required to validate and substantiate previous results. We sought to provide initial phenotypic analysis of a novel germline mutant allele. Our analysis provides a solid foundation for the future use of this allele to characterize gabra1 functionally and pharmacologically using zebrafish. We investigated the behavioral swim patterns associated with a nonsense mutation of the zebrafish gabra1 (sa43718 allele) gene. The sa43718 allele causes a decrease in gabra1 mRNA expression, which is associated with light induced hypermotility, one phenotype previously associated with seizure like behavior in zebrafish. Mutation of gabra1 was accompanied by decreased mRNA expression of gabra2, gabra3, and gabra5, indicating a reduction in the expression of additional α sub-units of the GABA_AR. Although multiple sub-units were decreased, larvae continued to respond to pentylenetetrazole (PTZ), indicating that a residual GABA_AR exists in the sa43718 allele. Proteomics analysis demonstrated that mutation of gabra1 is associated with abnormal expression of proteins that regulate synaptic vesicle fusion, vesicle transport, synapse development, and mitochondrial protein complexes. These data support previous studies performed in a zebrafish nonsense allele created by CRISPR/Cas9 and validate that loss of function mutations in the gabra1 gene result in seizure-like phenotypes with abnormal development of the GABA synapse. Our results add to the existing body of knowledge as to the function of GABRA1 during development and validate that zebrafish can be used to provide complete functional characterization of the gene.

2024-06-01·Acta Neuropathologica

Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex

Article

作者: Khodosevich, Konstantin ; Sørensen, Frederik N F ; Korshunova, Irina ; Mills, James D ; van Hecke, Wim ; Schubert, Dirk ; Riney, Kate ; Gaeta, Alessandro ; Palma, Eleonora ; Anink, Jasper J ; Lissner, Lilian J ; Aronica, Eleonora ; Ruffolo, Gabriele ; Jansen, Floor E ; Scheper, Mirte ; Mühlebner, Angelika

AbstractGABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

项与 GABRA2 相关的新闻（医药）

2024-07-14

·医药魔方

2024年6月 | 12款创新药进入III期，5款来自中国药企

根据全球临床试验收录网站clinicaltrials和中国临床试验登记平台chinadrugtrials，6月共12款创新药进入III期阶段，其中5款来自中国药企。这些在研药物覆盖靶点不乏HER2、PI3K、c-Kit等成熟靶点，也包括TIGIT、SIRPα、MDM2这类还未出现突破性进展的靶点。本文筛选其中9款重点产品加以介绍。注：1.信息来源于Clinicaltrials和Chinadrugtrials。 2.仅登记创新药，微创新和生物类似药不包括在内。 3.同一款药物在同一天启动多项III期临床，适应症合并记录；同一款药物在一个月内启动多项III期临床，以最早登记者准。 4.URAT1：尿酸转运蛋白1；SIRPα：信号调节蛋白α；PI3Kα：磷酸肌醇-3-激酶α；CK1ε：酪蛋白激酶1ε；OX2R：食欲素受体2；GABRA2：γ-氨基丁酸受体α2亚基；PSD95：突触后密度蛋白95；nNOS：神经元型一氧化氮合酶；MDM2：鼠双微粒体2。药物：IMM01 靶点：SIRPα 适应症：霍奇金淋巴瘤 IMM01（替达派西普）为宜明昂科自主研发的一款SIRPα-Fc融合蛋白，具有双重机制，能够同时阻断来自肿瘤的“别吃我”信号，并通过IgG1激活患者免疫系统的“吃我”信号。替达派西普在体内具有强大的抗肿瘤活性，临床上可以观察到单药的有效性。同时，在临床前体内药效试验中，替达派西普与靶向药物或免疫治疗药物联用，显示了针对血液肿瘤还有实体瘤的强大的抑瘤活性。 II期IMM01-04研究结果显示，33例既往接受PD-(L)1抗体治疗失败后的经典型霍奇金淋巴瘤（cHL）患者接受替达派西普联合替雷利珠单抗治疗后，客观缓解率（ORR）为65.6%（21/32），实现完全缓解（CR）的患者比例为18.8%（6/32），疾病控制率（DCR）达到了93.8%（30/32）。而且各个亚组分析的结果均显示，患者可以从联合治疗中获益。另外，替达派西普联合替雷利珠单抗治疗耐受性良好，没有患者发生因药物相关不良反应导致的永久停药情况。替达派西普于2019年8月进入I期临床阶段。截至目前，宜明昂科就该药物已申请了3项III期临床试验，分别针对经治cHL、初治骨髓增生异常综合征（MDS）、初治慢性粒-单核细胞白血病（CMML）。目前，全球共24款临床在研SIRPα靶向药物，其中替达派西普和evorpacept（ALX Oncology）是进展较快的两款产品。evorpacept也是一款SIRPα-Fc融合蛋白。 2022年1月，evorpacept联合曲妥珠单抗、雷莫西尤单抗和紫杉醇对比曲妥珠单抗联合雷莫西尤单抗和紫杉醇二线治疗HER2+胃癌患者的II/III期ASPEN-06研究启动。该研究的II期部分结果已于2023年10月公布。结果显示，evorpacept组患者经确认的总缓解率（ORR）为52%，而对照组这一数值为22%。此外，evorpacept组患者的中位缓解持续时间（mDOR）尚未达到，而对照组这一数字为7.4个月。药物：HZ-H08905 靶点：PI3Kα/CK1ε 适应症：外周T细胞淋巴瘤 HZ-H08905是和正医药开发的一款强效PI3Kα/CK1ε双重抑制剂，于2021年12月启动了首个I期临床试验。其临床结果已在美国血液学年会（ASH）2024上公布。截至2023年5月25日，该研究共纳入38例患者，其中包括26例复发或难治性T细胞淋巴瘤（R/R TCL）和12例复发或难治性B细胞淋巴瘤（R/R BCM）。接受每日1次50/100/200/300/450mg HZ-H08905治疗的患者数分别为1例、9例、14例、13例和1例。结果显示，在可评估疗效的35例患者中，ORR为60%，包括17%（6/35）CR、40%（14/35）部分缓解（PR）和3%（1/35）轻微缓解（MR），DCR为80%；mDOR和中位无进展生存期（mPFS）尚未达到，21例患者仍在接受治疗。此外，HZ-H08905在慢性淋巴细胞白血病（CLL）、弥漫性大B细胞淋巴瘤（DLBCL）、滤泡性淋巴瘤（FL）、套细胞淋巴瘤（MCL）、外周T细胞淋巴瘤（PTCL）和华氏巨球蛋白血症（WM）等多种非霍奇金淋巴瘤（NHL）亚型中表现出优异的抗肿瘤疗效，ORR范围为50%-100%，DCR范围为76%-100%。安全性方面，HZ-H08905在研究中尚未达到剂量限制性毒性（DLT），也未达到最大耐受剂量（MTD）。92%患者出现治疗相关不良事件（TRAE），发生率≥5%的≥3级TRAE为中性粒细胞减少（26.3%）、肺炎（7.9%）、白细胞减少（5.3%）、天冬氨酸转氨酶升高（5.3%）、丙氨酸转氨酶升高（5.3%）和带状疱疹（5.3%）。药物：barzolvolimab 靶点：c-Kit 适应症：慢性自发性荨麻疹 Barzolvolimab（CDX-0159）是Celldex Therapeutics开发的一款同类最佳（best in class）c-Kit单抗，于2019年10月进入临床阶段。下载Celldex AAAAI 2024大会PPT II期研究（NCT05368285）结果显示，慢性自发性荨麻疹（CSU）患者接受barzolvolimab治疗12周后，荨麻疹活动度评分（UAS7）显著下降。下载Celldex AAAAI 2024大会PPT 此外，barzolvolimab对未接受过或接受过奥马珠单抗治疗的患者均有不错的疗效。下载Celldex AAAAI 2024大会PPT 目前，全球共12款临床在研c-Kit靶向药物，其中barzolvolimab、bezuclastinib（Cogent Biosciences）和elenestinib（Blueprint Medicines）是进展最快的三款产品。bezuclastinib和elenestinib均是小分子c-Kit抑制剂，二者的首发适应症有所不同，前者为胃肠道间质瘤，而后者为系统性肥大细胞增生症。药物：BAY 2927088 靶点：EGFR exon 20/HER2 exon 20/EGFR C797S 适应症：非小细胞肺癌 BAY 2927088是拜耳开发的一款口服非共价可逆选择性酪氨酸激酶抑制剂，对携带EGFR和HER2突变（包括HER2 exon 20插入突变）的肿瘤有抑制活性。 I期研究结果显示，69例至少接受过一种系统治疗的非小细胞肺癌（NSCLC）患者接受BAY 2927088治疗后，整体人群ORR为26.0%(18/69)，其中携带HER2 exon 20突变的人群ORR为60.0%（12/20）。今年6月，BAY 2927088片和BAY 2927088溶液被CDE纳入突破性疗法，用于携带HER2（ERBB2）激活突变且既往接受过一种全身性治疗的不可切除或转移性NSCLC。药物：LP-003 靶点：IgE 适应症：季节性过敏性鼻炎 LP-003是天辰生物开发的一款抗IgE单抗，也是进度最快的国产抗IgE单抗。针对过敏性鼻炎的II期研究结果显示，100mg/200mg（每4周1次，共2次）LP-003组患者的花粉季峰值期间（PPP）鼻症状总分（TNSS）显著低于安慰剂组（3.17 vs. 3.45 vs. 4.25分，P<0.05）。此外，LP-003具有良好的安全性，其不良事件发生率与安慰剂组相似。报告的最常见不良事件（两组均>2%）为高尿酸血症、上呼吸道感染和鼻咽炎。目前，全球仅一款抗IgE单抗获批上市，即诺华的奥马珠单抗。在《中国变应性鼻炎诊断和治疗指南（2022年修订版）》中，抗IgE单抗是标准治疗仍不能充分控制的中重度季节性或常年性过敏性鼻炎患者的推荐治疗方案。全球在研抗IgE单抗并不多（仅7款），LP-003和ligelizumab（诺华）是唯二处于III期阶段的产品。全球在研抗IgE单抗（来源：医药魔方Nextpharma数据库） ligelizumab本是诺华计划开发的奥马珠升级版抗IgE单抗，其主推适应症同为荨麻疹和食物过敏。不过，在III期PEARL系列研究中，ligelizumab治疗CSU的效果不如奥马珠单抗。因此，诺华终止了ligelizumab治疗慢性诱导性荨麻疹（CIU）的III期PEARL-PROVOKE研究。令人遗憾的是，今年1月，诺华又终止了ligelizumab治疗花生过敏的III期研究，原因未作详细说明。药物：lutikizumab 靶点：IL-1β/IL-1α 适应症：化脓性汗腺炎 Lutikizumab（ABT-981）是艾伯维开发的一款抗IL-1α/IL-1β双抗，于2012年8月进入临床阶段。lutikizumab的开局并不顺利，先后放弃了在膝骨关节炎和手指关节炎上的探索。今年1月，lutikizumab治疗化脓性汗腺炎的II期研究迎来积极结果。lutikizumab（300mg，每2周1次）组达到HiSCR50（脓肿和炎性结节数量至少减少50%）的患者比例显著高于安慰剂组（59.5% vs. 35%，P=0.027）。化脓性汗腺炎是一种慢性、复发性、进行性、炎症性疾病，患者身上会形成疼痛的囊肿、脓肿和引流瘘管，最终导致不可逆转的皮肤损伤和残疾。全球约1%的人口患有化脓性汗腺炎。这种疾病的诊断不易，患者通常需要7-10年的时间才可确诊。目前，化脓性汗腺炎的治疗选择有限，仅包括司库奇尤单抗（诺华）、比吉利珠单抗（UCB）和阿达木单抗（艾伯维）。药物：belrestotug 靶点：TIGIT 适应症：非小细胞肺癌 Belrestotug是GSK以20.75亿美元自iTeos Therapeutics引进的一款抗TIGIT单抗。在针对NSCLC的II期GALAXIES Lung-201研究中，相比于dostarlimab（抗PD-1单抗）单药组，dostarlimab+belrestotug组患者的肿瘤消退具有临床意义。详细数据尚未公布。基于该积极结果，GSK启动了dostarlimab+belrestotug对比帕博利珠单抗单抗+安慰剂一线治疗NSCLC患者的III期GALAXIES Lung-301研究。除了NSCLC外，GSK也开展了dostarlimab+belrestotug对比dostarlimab一线治疗头颈部鳞状细胞癌（HNSCC）的II期研究。目前，全球共37款TIGIT靶向药物仍处于临床开发状态，其中6款已进入III期阶段，包括belrestotug、domvanalimab（吉利德）、rilvegostomig（阿斯利康）、tiragolumab（罗氏）、vibostolimab（默沙东）和欧司珀利单抗（百济神州）。药物：TAK-861 靶点：OX2R 适应症：发作性睡病猝倒 TAK-861是武田开发的一款OX2R激动剂，于2021年4月进入临床阶段。今年2月，TAK-861治疗1型发作性睡病的II期研究达到主要终点。结果显示，治疗第8周，与安慰剂组相比，TAK-861组患者的客观和主观觉醒指标改善效果均有统计学意义和临床意义。此外，Epworth嗜睡量表（ESS）和每周发作率（WCR）等关键次要终点的改善效果也具有显著的统计学意义和临床意义。发作性睡病（也称为嗜睡症）是一种慢性、罕见的中枢性嗜睡神经系统疾病，可分为1型发作性睡病（NT1）和2型发作性睡病（NT2）。前者是由于食欲素神经元大量缺失导致食欲素缺乏引起的，但后者的食欲素水平一般正常。刺激NT1患者的OX2R可恢复食欲素信号传导。药物：Y-3 靶点：GABRA2/PSD95/nNOS 适应症：缺血性卒中 Y-3是宁丹新药开发的一款nNOS/PSD95解耦联及GABRA2激动剂，可同时干预缺血性卒中后的神经元兴奋性损伤及突触可塑性改变。由于其靶点特异性高，Y-3也可减少NMDA及GABAA受体相关毒性。Y-3具有快速抗抑郁焦虑功能，有望成为首个卒中和卒中后抑郁兼顾同治的新型脑细胞保护剂。 II期研究结果表明，在发病48h内的缺血性脑卒中患者中，相比于安慰剂，Y-3（20/40/60mg，每日1次）能够提高达到90天良好功能预后的患者比例。 2023年8月，康哲药业与宁丹新药达成协议，获得了Y-3在中国大陆、香港特别行政区、澳门特别行政区的独家推广权。脑卒中是严重危害中国国民健康的重大非传染性疾病，中国总体卒中终生发病风险为39.9%，位居全球首位。2019年中国缺血性脑卒中新发人数约287万，1990年到2019年发病率大幅增长226.5%，患者人群规模大。脑卒中具有高致残率和高经济负担等特点，临床急需循证依据充分的药物减轻家庭和社会负担。推荐阅读 2024年5月 | 16款创新药进入III期，11款来自中国药企 2024年4月 | 20款创新药进入III期，11款来自中国药企 2024年3月 | 12款创新药进入III期，5款来自中国药企 2024年2月 | 15款创新药进入III期，5款来自中国药企 2024年1月 | 7款创新药进入III期，4款来自中国药企 2023年12月 | 13款创新药进入III期，6款来自中国药企 2023年11月 | 18款创新药进入III期，8款来自中国药企 2023年10月 | 28款创新药进入III期，9款来自中国药企 Copyright © 2024 PHARMCUBE. 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临床3期免疫疗法临床2期临床结果临床失败

2023-06-02

·PRNewswire

Terran Biosciences announces exclusive licensing deal with Pierre Fabre for idazoxan; Terran completes key development milestones

Terran obtains exclusive global development and commercialization rights for idazoxan, a late-stage clinical therapeutic for schizophrenia Development of novel XR formulation and GMP manufacturing completed to phase 3 standards First cohort dosed in clinical trial of XR idazoxan, early data demonstrate successful once-daily PK release profile FDA meeting completed, provided guidance on development path forward NEW YORK, June 2, 2023 /PRNewswire/ -- Terran Biosciences, Inc. ("Terran"), a CNS-focused biotech platform company, has entered into an agreement with French pharmaceutical company Pierre Fabre Médicament S.A.S ("Pierre Fabre") for worldwide exclusive rights to develop and commercialize a pipeline of Pierre Fabre's assets to treat neuropsychiatric illnesses. The deal features the novel lead compound idazoxan, a selective alpha 2 receptor antagonist, along with a portfolio of other compounds with a similar mechanism of action. Idazoxan has been tested in multiple phase 3 clinical studies and has been dosed in over 1,000 patients across a variety of neuropsychiatric indications. Phase 2 proof-of-concept trials have demonstrated idazoxan's safety and efficacy as adjunctive therapy in patients with schizophrenia, showing a statistically significant improvement in symptoms nearly double that of standard antipsychotic therapy alone. However, despite the promising safety and efficacy profile, idazoxan had a short half-life that required dosing 3 times daily to achieve the desired plasma levels and pharmacological effects, which restricted its development. Building on Pierre Fabre's Drug Master File, the Terran CMC team set out to solve the challenges around half-life and pharmacokinetics, and made a number of improvements to the process, resulting in innovative extended-release formulations ("idazoxan XR"), to enable once daily oral dosing with improved ease of use. In previous trials, idazoxan was dosed as a racemic compound (a mixture of half R-idazoxan and S-idazoxan); however, only one of the enantiomers is considered active at the target receptor. Terran has now manufactured enantiomerically pure idazoxan to phase 3 standards and has developed five new clinical drug product forms of idazoxan XR, including pure R-idazoxan, pure S-idazoxan, and racemic idazoxan with different release profiles. The five new forms of idazoxan XR are currently being evaluated in an ongoing multisite phase 1 clinical trial in which Terran plans to enroll more than 100 healthy volunteers. The first cohort of subjects in this trial has been dosed, and early analysis of the results demonstrate the intended once-daily pharmacokinetic profile has successfully been achieved. Further study results will confirm which optimized form and dose to take forward into the planned phase 2 study in over 200 patients with schizophrenia. Terran also recently completed a meeting with the FDA confirming that, pending analysis of the final study data, the design of the current study should enable the use of any of the selected XR formulations in the larger phase 2 study. Dr. Sam Clark, Terran's founder and CEO remarked, "We are thrilled to partner with the team at Pierre Fabre and to push forward with the development of idazoxan and this pipeline of CNS compounds. Given the strength of the human data to date, we believe idazoxan XR has the potential to revolutionize the treatment of patients with schizophrenia and other neuropsychiatric disorders." About Terran Biosciences, Inc. Terran is a biotech platform company developing a portfolio of therapeutics and technologies for patients with neurological and psychiatric diseases. Backed by a number of life-science and tech investors, Terran has built a CNS-focused, tech-enabled drug development platform, and is rapidly advancing a number of late-stage assets, which include novel psychedelic-based therapeutics. Terran Contact Investor Relations: [email protected] Media: [email protected] Licensing and Partnerships: [email protected] SOURCE Terran Biosciences, Inc.

临床2期临床3期引进/卖出临床1期